ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.516G>A (p.Lys172=)

dbSNP: rs80359790
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044583 SCV000072596 uncertain significance Hereditary breast ovarian cancer syndrome 2021-11-07 criteria provided, single submitter clinical testing This sequence change affects codon 172 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and ovarian cancer and/or urothelial cancer (PMID: 19267246, 31263571). ClinVar contains an entry for this variant (Variation ID: 51795). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 6 and/or exons 5-6 and introduces a premature termination codon (PMID: 19267246). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113726 SCV000327154 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023653 SCV001185564 likely pathogenic Hereditary cancer-predisposing syndrome 2022-12-16 criteria provided, single submitter clinical testing The c.516G>A variant (also known as p.K172K), located in coding exon 5 of the BRCA2 gene, results from a G to A substitution at nucleotide position 516. This nucleotide substitution does not change the at codon 172. This alteration was identified in a Danish patient with breast cancer diagnosed at 37 and 65 years old; her family history was significant for male breast cancer in her father and ovarian cancer in a paternal aunt (Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50). This alteration was detected in a patient with urothelial cancer (Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. Splicing assays have shown this variant to result in nonsense-mediated decay prone transcripts that lack coding exons 4 and 5 (Ambry internal data; Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284089 SCV001469688 uncertain significance not provided 2021-03-18 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000044583 SCV002025893 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001284089 SCV004242682 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000113726 SCV004833253 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-12-14 criteria provided, single submitter clinical testing The c.516G>A (p.Lys172=) synonymous variant in the BRCA2 gene is located at exon 6 and is predicted to inflict donor loss (SpliceAI delta score: 0.84), resulting in alternative splicing and disrupted protein product. The variant has been reported in 4 unrelated individuals with breast/ovarian/urothelial cancer (PMID: 19267246, 35464868, 31263571). Patient RNA analysis and mini gene assay showed abnormal splicing that led to nonsense-mediated decay (PMID: 19267246). The variant is absent in the general population database (gnomAD). Therefore, the c.516G>A (p.Lys172=) variant of BRCA2 has been classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000044583 SCV004848359 likely pathogenic Hereditary breast ovarian cancer syndrome 2020-06-19 criteria provided, single submitter clinical testing The p.Lys172Lys variant in BRCA2 has been identified in one individual with breast cancer (Hansen 2009 PubMed: 19267246) and was absent from large population studies. Exon trapping and RT-PCR analysis showed that this variant results in skipping of exon 6 and of exon 5 and 6. The skipping results in a frameshift and a premature termination at codon 154 (skipping of exon 5 and 6) or codon 168 (skipping of exon 6), which most likely will result in nonsense-mediated mRNA decay (NMD) (Hansen 2009 PubMed: 19267246). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PS3.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000113726 SCV005045988 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2024-05-27 criteria provided, single submitter clinical testing PP1; PVS1_Strong; PM2_Supporting
Breast Cancer Information Core (BIC) (BRCA2) RCV000113726 SCV000147045 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2001-10-29 no assertion criteria provided clinical testing
Cancer Genomics Lab, PINUM Cancer Hospital RCV000044583 SCV004011751 pathogenic Hereditary breast ovarian cancer syndrome 2022-05-23 no assertion criteria provided clinical testing

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